Functional Consequences of Developmental Myosin II Down-regulation in Neurons

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DESCRIPTION (provided by applicant): Developing neurons undergo complex changes in gene expression that translate into mechanistic differences in how the neuron functions. The majority of studies aimed at understanding the mechanisms of axon extension, as they relate to regenerative attempts, are based on studies of early embryonic neurons due to technical issues. In the proposed research I address the cytoskeletal basis of changes that occur in the mechanism of axon extension as dorsal root ganglion sensory neurons transition from early to late developmental stages. The mechano-enzyme myosin II has been determined to be a major component of the mechanism of axon extension and guidance of early embryonic axons. Our preliminary data demonstrate that myosin II is down- regulated in late stage sensory neurons, and that late stage neurons utilize a mechanism of axon extension independent on the function of the mechano-enzyme myosin II for axon extension. In addition, late stage neurons fail to undergo guidance in myosin II-dependent assays, unlike early stage neurons. The major aim of the research proposed is to determine if the mechanism of axon extension in late stage neurons can be "rejuvenated" by experimental re-expression of myosin II. The results of these studies will determine whether re-expression of myosin II in late stage neurons has the potential to revert the mechanisms of axon extension and guidance to those utilized by early embryonic neurons. Recovery from Injury to the nervous system is a major societal issue, particularly affecting populations with higher incidence of violent behavior. The long term goal of these studies is to provide information relevant to the promotion of axon regeneration in injured individuals by determining how the mechanism of axon extension changes during development and whether these changes can be reverted to generate neurons with increased regenerative potential. Mounting evidence indicates that the mechanisms of axon extension and guidance are developmentally regulated. In this proposal I seek to elucidate the functional consequences of the developmental downregulation of myosin II expression in sensory neurons and determine if older neurons can be "rejuvenated" by re-expression of myosin II.